Deposits of misfolded proteins in cells or in intracellular space are found to play a role in a number of severe medical disorders, among which are diseases such as Alzheimer's, Parkinson's, and type-2 diabetes. The costs incurred by the health care systems worldwide for treating those medical conditions are massive, as is the impact onto the lives of those that are affected and their families.
The number of cases is likely to increase steadily as life expectancy rises. To address this growing problem, new therapies are being developed based on interfering at early stages with the ability of proteins to form aggregates.
The typical life cycle of a protein in the cell begins with synthesis of the polypeptide at the ribosome and continues from an initially unfolded state via a folding pathway, which might involve one or several folding intermediates, to the biologically-active native state of the protein. For most proteins, this native state corresponds to a closely folded conformation, although some exceptions exist, one of which is α-synuclein, which is natively unfolded (Uversky V N (2002) Natively unfolded proteins: A point where biology waits for physics, Protein Sci. 11:739-756). The life cycle ends with denaturation and degradation.
The cell possesses sophisticated quality control mechanisms that assist the folding process of the protein. The first of these is the ribosome itself. In the second, the protein is supported by heat shock proteins and chaperones that act as catalyst or promoter to fold a protein in the correct way, or to refold misfolded proteins (Evans M S, Clarke T F IV, Clark P L (2005) Conformations of Co-Translational Folding Intermediates, Prot, Pept. Let. 12(2): 189-195).
In the case that refolding fails, misfolded proteins are processed by the ubiquitin-proteasome system. In a first step, ubiquitin is being attached to faulty structures. These tags mark the polypeptide chain for degradation and this task is fulfilled by the proteasome. A more detailed description of folding and misfolding processes can be found in Dobson C M (2003) Protein folding and misfolding, Nature 426: 884-890 and Vendruscolo M, Zurdo J, MacPhee C E, Dobson C M (2003) Protein folding and misfolding: a paradigm of self-assembly and regulation in complex biological systems, Phil. Trans. R. Soc. Lond. A 361: 1205-1222).
However, the quality control of the cell can fail for a variety of reasons, leading to accumulation of misfolded proteins. These proteins can then aggregate forming dense structures called amyloid fibrils with a core region consisting of continuous assemblies of β-sheets (Dobson C M (2005) Prying into prions, Nature 435: 747-749).
In living tissue, protein deposition (often in the form of amyloid aggregates) is frequently associated with a variety of diseases, many of which are age related. For example, these diseases include neurodegenerative diseases such as Parkinson's, Alzheimer's and spongiform encephalopathies, as well as systemic (such as immunoglobulin light chain or transthyretin amyloidoses) and peripheral tissue disorders (such as type-2 diabetes). In humans, more than 30 different disorders are known to be associated with protein deposition.
Particularly in the developed world, where the life expectancy continues to rise steadily, the ever-growing number of people affected with those diseases poses unprecedented and increasingly severe problems to society.
It is estimated that in the United States alone about 4.5 million people were affected by Alzheimer's disease in 2000, and the number of cases might rise to 16 million by 2050 (Hebert L E, Scherr P A, Bienias J L, Bennett D A, Evans D A (2003) Alzheimer Disease in the U.S. Population: Prevalence Estimates Using the 2000 Census, Arch. Neurol. 60: 1119-1122). The risk of people being affected with this neurodegenerative disease is estimated to be as high as 1 in 10 for people over 60 years of age and almost 1 in 2 for those over 85 (Evans D A, Funkenstein H H, Albert M S, Scherr P A, Cook N R, Chown M J, Hebert L E, Hennekens C H, Taylor J O (1989) Prevalence of Alzheimer's Disease in a Community Population of Older Persons. Higher than Previously Reported, Jama 262: 2551-2556). The impact onto the health systems is immense, and some authors predict that neurodegenerative diseases could become the leading cause of death (Lozano A M, Kalia S K (2005) New Movements in Parkinsons's, Sci. Am., 291(1): 58-65).
Furthermore, the propensity of biomolecules to form aggregates in solution has always been one of the major problems in drug design. Therapeutic molecules must be both soluble as well as reactive and should not form aggregates when administered in relatively high concentrations or stored over long periods of time. In many cases, finding conditions in which such polypeptides are sufficiently stable proves to be time consuming and costly, and sometimes even impossible with currently available methods. Finding ways to interfere with the folding process in order to impede the formation of aggregates can therefore improve the efficiency of drug development.